1/8: INIA Stress and Chronic Alcohol Interactions: Role of Dynorphin/KOR and Oxytocin Systems in Stress-Enhanced Alcohol Drinking, Relapse, and Impaired Behavioral Flexibility

1/8：INIA 压力和慢性酒精相互作用：强啡肽/KOR 和催产素系统在压力增强的饮酒、复发和行为灵活性受损中的作用

• 批准号: 10408532
• 负责人: HOWARD C. BECKER
• 金额: $ 45.25万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10408532
• 关键词: Address; Alcohol consumption; Alcohols; Amygdaloid structure; Area; Behavior; Behavioral; Brain; CRISPR/Cas technology; Choice Behavior; Chronic; Chronic stress; Complex; Data; Development; Dynorphins; Economic Burden; Ethanol; Funding; Genetic; Goals; Health; Hypothalamic structure; Impairment; Infusion procedures; Injections; Internal Ribosome Entry Site; Knowledge; Mediating; Modeling; Mus; Neurons; Neuropeptides; Odors; Operant Conditioning; Outcome; Outcome Measure; Oxytocin; Oxytocin Receptor; Pathway interactions; Peptides; Pharmacology; Pilot Projects; Population; Predisposition; Procedures; Quinine; Receptor Signaling; Relapse; Research Project Grants; Rewards; Role; Self Administration; Sex Differences; Signal Transduction; Stress; Sucrose; Swimming; System; Testing; Transgenic Mice; United States; Viral; Work; alcohol exposure; alcohol relapse; alcohol seeking behavior; alcohol use disorder; antagonist; behavior measurement; behavioral impairment; drinking; effective intervention; flexibility; individual variation; insight; kappa opioid receptors; mouse model; neural circuit; response; social; stress management; stressor; time use

PROJECT SUMMARY Stress is known to be a significant factor in triggering relapse, promoting heavy alcohol (ethanol) consumption, and producing adaptations that reduce behavioral flexibility, thereby compromising control over alcohol drinking and elevating susceptibility to relapse. Unfortunately, mechanisms and neurocircuitry underlying the complex interaction between stress and alcohol drinking are not well understood. As part of the INIAstress Consortium, we developed a mouse model in which repeated brief forced swim stress (FSS) exposure interacts with chronic intermittent ethanol (CIE) exposure to selectively enhance alcohol drinking in dependent (CIE-exposed) mice. During the current funding period we established a role for the pro-stress neuropeptide dynorphin/kappa opioid receptor (DYN/KOR) system in stress-enhanced alcohol drinking. At the same time, we used operant conditioning procedures to demonstrate that the anti-stress neuropeptide oxytocin (OT) reduced alcohol self- administration and stress-induced relapse-like behavior. This research project focuses on the role of DYN/KOR and OT systems within stress-relevant circuits in models demonstrating the ability of stress to interact with chronic alcohol in promoting escalation of alcohol drinking, enhanced relapse-like behavior, and impaired behavioral flexibility. The project will employ two stressors (forced swim stress (FSS) and predator odor (TMT) exposure), two models of stress-alcohol interactions (CIE-FSS Drinking and stress (TMT)-induced operant alcohol relapse seeking/drinking), and two measures of behavioral (in)flexibility (alcohol-biased choice behavior and persistence of alcohol drinking despite aversion). Building on our previous work demonstrating an important role for DYN/KOR activity in the central amygdala (CeA) and pilot data showing strong DYN input to the CeA from the insular cortex (a stress and alcohol sensitive cortical area), studies will examine the role of DYN/KOR signaling in insular cortical (IC) projections to the CeA (IC-CeADYN pathway). Other pilot data suggest that the stress-buffering effects of OT may be mediated by signaling in the CeA. Thus, studies will examine OT activity in hypothalamic (PVN) projections to the CeA (PVN-CeAOT pathway). Further, studies will examine the potential unique interactive effects of the DYN/KOR and OT systems in the PVN on behavioral consequences of stress-alcohol interactions. The general experimental strategy will entail utilizing transgenic mice and pharmacological, chemogenetic, and CRISPR/Cas9 approaches to target manipulation of these neuropeptides in specific neurons within these specific neurocircuits. Collectively, these studies focus on adaptations in pro-stress (DYN/KOR) and anti-stress (OT) systems within stress-relevant neurocircuits using different stressors and different drinking models, thereby directly interfacing with the overall thematic framework of the consortium. The ultimate goal is to gain new knowledge that will inform development of more effective interventions for treating stress-related excessive alcohol drinking and relapse.

项目摘要 已知压力是触发复发，促进大量酒精（乙醇）消费量的重要因素 并产生改编以降低行为灵活性，从而损害对饮酒的控制 并提高复发的敏感性。不幸的是，该复合物为基础的机制和神经循环 压力和饮酒之间的相互作用尚不清楚。作为无罪分子财团的一部分， 我们开发了一个鼠标模型，其中重复的简短强迫游泳应力（FSS）暴露与慢性相互作用 间歇性乙醇（CIE）暴露于有选择地增强依赖（CIE暴露）小鼠的饮酒。 在当前的资助期间 压力增强饮酒的受体（Dyn/Kor）系统。同时，我们使用了操作员 调节程序，以证明抗压力神经肽催产素（OT）降低酒精自我 给药和压力引起的复发样行为。该研究项目的重点是Dyn/Kor的角色 在模型中，与应力相关的电路中的OT系统证明了压力与与之相互作用的能力 慢性酒精在促进饮酒升级，类似复发的行为和损害方面升级 行为灵活性。该项目将采用两个压力源（强迫游泳应力（FSS）和捕食者气味（TMT） 暴露），两种模型的应力 - 酒精相互作用（CIE-FSS饮用和压力（TMT）诱导的操作者 酒精复发寻求/饮酒）和两种行为（in）灵活性的措施（酒精偏见的选择行为 尽管厌恶，饮酒的持续存在）。以我们以前的工作为基础，证明了一个重要的 Dyn/Kor活动在中央杏仁核（CEA）和飞行员数据中的作用，显示了CEA的强大输入 从岛状皮质（压力和酒精敏感的皮质区域）中，研究将检查Dyn/Kor的作用 对CEA（IC-Ceadyn途径）的岛状皮质（IC）投影中的信号传导。其他飞行员数据表明 OT的压力缓冲作用可以通过CEA中的信号传导介导。因此，研究将检查OT 下丘脑（PVN）对CEA（PVN-CEAOT途径）的活性。此外，研究将检查 PVN中Dyn/Kor和OT系统对行为的潜在独特互动效果 压力 - 酒精相互作用的后果。一般的实验策略将需要使用转基因 小鼠和药理学，化学发生和CRIS/CAS9靶向操作的方法 这些特定神经环节中特定神经元中的神经肽。这些研究集体关注 使用压力（DYN/KOR）和反压力（OT）的适应性适应应力与应力神经回路的适应 不同的压力源和不同的饮酒模型，因此直接与整个主题框架接口 财团。最终目标是获取新知识，以使开发更有效 治疗与压力相关的过度饮酒和复发的干预措施。